2-[p-(phenylsulfonyl) phenyl]-1, 3-indanedione and its tautomer



Patented Dec. 5, 1967 3 356 732 Alternatively, the solid keto form can be dissolved in a olar solvent which v ts th k t for to the enol 2 PHENYLSULFofiYII HENY J,3-INDANE- f C n H e e o m DIONE AND ITS TAUTOMER Hans-Dieter Becker, Schenectady, N.Y., assignor to General Electric Company, a corporation of New When dissolved in polar solvents, and especially hydroxylic solvents, e.g., alcohols, the compound ionizes York forming the enolate ion. As such it will form salts with No Drawing, Fil d M 29, 1966, S N 533,240 aqueous metal hydroxides or metal alcoholates to form 3 Claims. (Cl. 260590) the corresponding metal salts, e.g., the alkali and alkaline earth metal salts, etc. This invention relates to the chemical compound 2-[p- When acid is added to an alcohol solution of the com- (phenylsulfonyl)phenyl] 1,3 -indanedione which in the pound, an equilibrium between the enol and keto forms solid state exists in its enol form which can be named 3- is established until suflicient acid is added that the hydrohydroxy- -[p-(phenylsulfonyl)phenyl]-1-indenone. gen ion from the acid drives the equilibrium to the point In the search for chemical compounds having anticoagwhere all of the compound is in the keto form as shown ulant activity in blood, many 1,3-indanedione compounds by the equation.

have been investigated. In evaluating the usefulness of When dissolved in non-polar solvents, e.g., ethers, these compounds as anticoagulants, their effectiveness is chloroform, benzene, etc., the compound exists in the usually compared with that of bishydroxycoumarin, genketo form. In the solid state, the enol form is intense red erally known as dicumarol, the first clinically developed in color and in solution forms deep yellow to orange solucoumarin derivative found useful as an anticoagulant. The tions. In either the solid state or in solution, the keto form therapeutic activity of these compounds depends upon the is essentially colorless, with any color being due to the ability to prolong the prothrombin time by suppression of presence of a slight amount of the enol form. Therefore, the formation of prothrombin by the liver. the particular form that the compound is in is readily Many of the 1,3-indanedione compounds, which have determined by its color. If both the enol and keto forms are been used for anticoagulants, have relatively short durapresent in solution, as for example in an acidified alcohol tion of activity and therefore, require that they be adminsolution, the color is dependent upon the concentration istered frequently. Therefore, it is desirable to have a of the enol form present. Addition of more acid will cause chemical compound which will have high activity as an the solution to become less colored. In the ultraviolet reanticoagulant, and also will retain this activity for a relagion of the spectra, the enol form shows strong absorptively long time. Such a compound would require relation in the region of 370 mu which decreases as the equitively small doses to be given, no more than once a day, librium is shifted to the keto form, thus providing a conto maintain a given level of anticoagulant activity in the 40 venient method of determining the amount of each form blood. present in solution.

I recently synthesized the new chemical compound 2- The tautomerism that exists between these compounds is [p-(phenylsulfonyl)pheuyl]-1,3-indanedione. In the solid shown below with the characteristics of each.

Enol Form Keto Form Formula Name ti-lydroxy-2-[p-(phenylsnlfonyl)phenyl1-1- 2-[p-(phenylsulfonyl)-phenyl]-1,3-indanedione 1n enone Color ruby red colorless Existence In crystalline state and as enolate ion, in polar In molten state, in supercooled state, in solution in solvents in absence of acids. Presence of acids non-polar solvents andin acidified polar solvents.

cause shift towards keto form.

state, this compound exists in' its tautomeric enol form The enol form of this compound, when administered to as ruby red crystals, but changes almost completely to the rhesus monkeys, was shown to have high activity as an keto form at its melting point forming a light yellow melt. anticoagulant, as shown by the increase in prothrombin This melt readily supercools to a light yellow solid thereby time. This activity was retained over a relatively long pefreezing the compound in its keto form. In order to rapidly riod of time. reconvert the solid keto form of the compound to the enol 7 In order that those skilled in the art may better underform, the keto form should be held at a temperature slightstand my invention, the following examples are given by 1y below the melting point until the enol form crystallizes. way of illustration and not by way of limitation. In the Example 1 This example illustrates the synthesis of 2-[p-(phenylsulfonyl)phenyl]1,3-indanedione. A solution of 11.6 g. of phenyl-p-tolylsulfone in 200 ml. of anhydrous dimethylformamide was prepared. While stirring the mixture by means of a stream of nitrogen, 12.0 g. of potassium-t-butoxide was added rapidly producing a deep, red solution. To this solution, ml. of diethylphthalate wasadded dropwise to regulate the exothermic reaction which occuts; The dark green colored reaction mixture was agitated with nitrogen for 1 hour, after which 500 ml. of ice water was added, whereupon the reaction mixture became orange-red in color. After extracting with 100 ml. of ether to remove unreacted starting material, the aqueous layer was acidified with a mixture of 40 ml. of concentrated hydrochloric acid and 60 ml. of water, and shaken with 100 ml. of ether which was not removed. A deep red, solid remained dispersed in the aqueous layer and was removed by filtration. This precipitate, weighing 16.4 g., was recrystallized by dissolving in boiling chloroform and adding absolute methanol, to produce 8.6 g. of recrystallized ruby red crystals, identified as the enol form of 2-[p-(phenylsulfonyl)phenyl]-1,3-indanedione, having a melting point of 197198 C. At and above its melting point, the compound became a light yellow melt which again became ruby red on crystallizing, when held slightly below its melting point. Quick cooling gave a slight yellow solid of the keto form. Elemental analysis showed that it contained 69.44% carbon, 3.83% hydrogen and 8.71% sulfur, compared to theoretical values of 69.61% carbon, 3.89% hydrogen and 8.85% sulfur for C H O S.

These red crystals of the enol form are slightly soluble in ether and benzene and readily soluble in chloroform forming colorless solutions of the keto form. The red crys tals dissolve in aqueous sodium hydroxide to form a deep yellow solution of the sodium salt. Solutions of the enol form in polar solvents, for example, dimethylsulfoxide, methanol, etc., are intense yellow. The methanol solution will become progressively lighter in color as aqueous hydrochloric acid is added incrementally, and finally be- 4 Examzple 2 Clinical tests on white mice (Taconic Swiss) showed that the 2 [p (phenylsulfonyl)phenyl]-l,3-indanedi-one was not lethal when tested in doses up to as high as 100 rug/kg. The solid enol in sufficient aqueous 0.5% methylcellulose to form a suspension was intravenously injected.

Example 3 A rather large dose of 25 rug/kg. of the solid enol form of 2-[p-(phenylsulfonyl)phenyl]-l,3-inda.nedione, in sufficient 0.5 aqueous methylcellulose to form a suspension, was administered orally to a rhesus monkey. Table I shows the prothrombin time measured in seconds, determined on samples of the blood, taken before administration (control) of the 2-[p-(phenylsulfonyl)phenyl]-1,3-indanedione and at the specified time, as shown in the table, after administration of this material.

TABLE I Prothrombin time,

seconds Control 15.4 lhour 15.9 6 hours 15.9 1 day 22.6 2 days 26.0 3 days 47.2 5 days 42.6 7 days 42.9

This example illustrated that Z-[p-(phenylsulfonyl) phenyl]-1,3-indanedione had considerable anticoagulant activity as demonstrated by the increase prothrombin time and that this activity, once initiated, was sustained, over a long period of time.

Example 4 This example compares the anticoagulant activity of 2-[p-(phenylsulfonyl)phenyl]-1,3-indanedione with bishydroxycoumarin, a material widely used because of its anticoagulant activity. In this example, the compounds were administered orally to rhesus monkeys and the prothrombin time at various times determined, as in Example 3. The results are shown in Table II.

TABLE II PBOTHROMBIN TIME Bishydroxyeoumarin, total 2-[p-(phenylsulfonyD- dose 25 mg. (9.51 mgJkg.) pheny1]-1,3-indanedione, total dose 25 mg. (8.59 rug/kg.)

- Increase Percent Increase Percent Seconds Over Increase Seconds ver Increase Control Over Control Over Control Control comes colorless. By use of these techniques, it is very easy to convert one tautomer into the other.

Other alkyl esters of phthalic acid can be used in place of diethylphthalate, and other alkoxides other than potassium-t-butoxide can be used in producing this compound, for example, the alkali metal alkoxides of the lower alkyl alcohols. This compound may also be made by reaction of p-(phenylsulfonyDphenyl acetic acid with phthalic anhydride or the esters of these two reactants or by a condensation of p-(phenylsulfonyl)benzaldehyde with phthalide.

in the form of its non-toxic metal salts, preferably its sodium salt. It is not clear whether it is the enol or keto form which actually functions as the anticoagulant, but anticoagulant activity of 1,3-indanediones appear to be related to their ability to tautomerize and have both a keto and enol form. Likewise, this compound can be incorporated in various pharmaceutical preparations, such as tablets, capsules, etc. and may be mixed in suitable proportions with non-toxic pharmaceutical carriers, such as starches, gums, sugars, etc.

Obviously, other modifications and variations of the present invention are possible in light of the above techings. It is therefore to be understood that changes may be made in the particular embodiments herein mentioned and described, which are within the full intended scope of the 15 218997358 invention as described by the appended claims.

6 What I claim as new and desire to secure by Letters Patent of the United States is:

l. The tautomeric compounds corresponding to the empirical formula C H O S selected from the group con- 5 sisting of 3-hydroxy 2 [p-(phenylsulfonyl)phenyl]-1- indenone and 2-[p-(phenylsulfonyl)phenyl]-1,3-indanedione.

2. The tautomer of claim 1 having the name 3-hydroxy- 2- [p-(phenylsulfonyl) phenyl] -1 -indenone.

3. The tautomer of claim 1 having the name Z-[p- (phenylsulfonyl)phenyl] -1,3 -indanedi0ne.

References Cited UNITED STATES PATENTS 8/1959 Sperber 16765 DANIEL D. HORWITZ, Primary Examiner. 

1. THE TAUTOMERIC COMPOUNDS CORRESPONDING TO THE EMPIRICAL FORMULA C21H14O4S SELECTED FROM THE GROUP CONSISTING OF 3-HYDROXY - 2 - (P-(PHENYLSULFONYL)PHENYL)-1INDENONE AND 2-(P-(PHENYLSULFONYL)PHENYL)-1,3-INDANEDIONE. 